Throughout this application, various publications are referenced in parentheses by author and year. Full citations for these references may be found at the end of the specification immediately preceding the sequence listings and the claims. The disclosure of these publications in their entireties are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
Melanin-concentrating hormone (MCH) is a cyclic peptide originally isolated from salmonid (teleost fish) pituitaries (Kawauchi et al., 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of xcex1-MSH. Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al., 1996). Its role in feeding or body weight regulation is supported by a recent Nature publication (Qu et al., 1996) demonstrating that MCH is overexpressed in the hypothalamus of ob/ob mice compared with ob/+ mice, and that fasting further increased MCH mRNA in both obese and normal mice during fasting. MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al., 1997). MCH also has been reported to functionally antagonize the behavioral effects of xcex1-MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al., 1997); in addition, stress has been shown to increase POMC mRNA levels while decreasing the MCH precursor preproMCH (ppMCH) mRNA levels (Presse et al., 1992). Thus MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al., 1996).
Although the biological effects of MCH are believed to be mediated by specific receptors, binding sites for MCH have not been well described. A tritiated ligand ([3H]-MCH) was reported to exhibit specific binding to brain membranes but was unusable for saturation analyses, so neither affinity nor Bmax were determined (Drozdz and Eberle, 1995). Radioiodination of the tyrosine at position thirteen resulted in a ligand with dramatically reduced biological activity (see Drozdz and Eberle, 1995). In contrast, the radioiodination of the MCH analogue [Phe13,Tyr19]-MCH was successful (Drozdz et al., 1995); the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7), PC12, and COS cells. In G4F-7 cells, the KD=0.118 nM and the Bmax xcx9c1100 sites/cell. Importantly, the binding was not inhibited by xcex1-MSH but was weakly inhibited by rat ANF (Ki=116 nM vs. 12 nM for native MCH) (Drozdz et al., 1995). More recently specific MCH binding was reported in transformed keratinocytes (Burgaud et al., 1997) and melanoma cells (Drozdz et al., 1998), where photo-crosslinking studies suggest that the receptor is a membrane protein with an apparent molecular weight of 45-50 kDaltons, compatible with the molecular weight range of the GPCR superfamily of receptors. No radioautoradiographic studies of MCH receptor localization using this ligand have been reported as yet.
The localization and biological activities of MCH peptide suggest that the modulation of MCH receptor activity may be useful in a number of therapeutic applications. The role of MCH in feeding is the best characterized of its potential clinical uses. MCH is expressed in the lateral hypothalamus, a brain area implicated in the regulation of thirst and hunger (Grillon et al., 1997); recently orexins A and B, which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al., 1998). MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Hervxc3xa9 and Fellman, 1997); after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA (Bahjaoui-Bouhaddi et al., 1994). Consistent with the ability of MCH to stimulate feeding in rats (Rossi et al., 1997) is the observation that MCH mRNA levels are upregulated in the hypothalami of obese ob/ob mice (Qu et al., 1996), and decreased in the hypothalami of rats treated with leptin, whose food intake and body weight gains are also decreased (Sahu, 1998). MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al., 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.
In all species studied to date, a major portion of the neurons of the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called xe2x80x9cextrapyramidalxe2x80x9d motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al., 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson""s disease and Huntingdon""s Chorea in which extrapyramidal circuits are known to be involved.
Human genetic linkage studies have located authentic hMCH loci on chromosome 12 (12q23-24) and the variant hMCH loci on chromosome 5 (5q12-13) (Pedeutour et al., 1994). Locus 12q23-24 coincides with a locus to which autosomal dominant cerebellar ataxia type II (SCA2) has been mapped (Auburger et al., 1992; Twells et al., 1992). This disease comprises neurodegenerative disorders, including an olivopontocerebellar atrophy. Furthermore, the gene for Darier""s disease, has been mapped to locus 12q23-24 (Craddock et al., 1993). Dariers"" disease is characterized by abnormalities I keratinocyte adhesion and mental illnesses in some families. In view of the functional and neuroanatomical patterns of the MCH neural system in the rat and human brains, the MCH gene may represent a good candidate for SCA2 or Darier""s disease. Interestingly, diseases with high social impact have been mapped to this locus. Indeed, the gene responsible for chronic or acute forms of spinal muscular atrophies has been assigned to chromosome 5q12-13 using genetic linkage analysis (Melki et al., 1990; Westbrook et al., 1992). Furthermore, independent lines of evidence support the assignment of a major schizophrenia locus to chromosome 5q11.2-13.3 (Sherrington et al., 1988; Bassett et al., 1988; Gilliam et al., 1989). The above studies suggest that MCH may play a role in neurodegenerative diseases and disorders of emotion.
Additional therapeutic applications for MCH-related compounds are suggested by the observed effects of MCH in other biological systems. For example, MCH may regulate reproductive functions in male and female rats. MCH transcripts and MCH peptide were found within germ cells in testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al., 1996). MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al., 1996). In ovariectomized rats primed with estradiol, MCH stimulated luteinizing hormone (LH) release while anti-MCH antiserum inhibited LH release (Gonzalez et al., 1997). The zona incerta, which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al., 1984). MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin. MCH analogues may also be useful in treating epilepsy. In the PTZ seizure model, injection of MCH prior to seizure induction prevented seizure activity in both rats and guinea pigs, suggesting that MCH-containing neurons may participate in the neural circuitry underlying PTZ-induced seizure (Knigge and Wagner, 1997). MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al., 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996). Together with anatomical data reporting the presence of MCH in fluid regulatory areas of the brain, the results indicate that MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
As used in this invention, the term xe2x80x9cantagonistxe2x80x9d refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist. In the case of a G-protein coupled receptor, activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed. Some specific, but by no means limiting, examples of well-known second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis. Conversely, the term xe2x80x9cagonistxe2x80x9d refers to a compound which binds to, and increases activity of, a receptor as compared with the activity of the receptor in the absence of any agonist.
In one embodiment of this invention, the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCH1) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vitro assays is disclosed. The in vitro receptor binding and activation assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
Furthermore, the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa), sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCH1 receptor may be beneficial. In addition, the compounds of the present invention may be used to reduce the body mass of a subject.
This invention provides a compound having the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or xe2x80x94CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)nNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR7; or xe2x80x94OR3; or wherein R1 and R2 together may form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein the dashed line represents a single bond or a double bond;
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CON(R3)2;
wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R7 is H; F; Cl; Br; I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R8 is independently straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl may be substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention further provides a compound having the structure: 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94SR3; xe2x80x94CO2R3; or xe2x80x94OR3;
wherein each R1 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein each R2 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; or aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2)n, O, S or NR3;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein m is an integer from 0 to 4 inclusive;
wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention also provides a compound having the structure: 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CON(R3)2;
wherein each R1 is independently xe2x80x94H; F; Cl; Br; I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)nNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR5; xe2x80x94OR3; or wherein R1 and R2 together form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; O; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; O; C(R3)2; or NR3;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; xe2x80x94XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R7 is xe2x80x94H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)nNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR5; xe2x80x94OR3; or wherein R1 and R2 together form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; O; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; O; C(R3)2; or NR3;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; xe2x80x94XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R7 is xe2x80x94H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94OR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject""s depression and/or anxiety.
This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of: 
This invention further provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
This invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
This invention further provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier. This invention further provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
This invention provides a compound having the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or xe2x80x94CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)pNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR7; xe2x80x94OR3; or wherein R1 and R2 together form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein the dashed line represents a single bond or a double bond;
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CON(R3)2;
wherein each V is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R6 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; (CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R7 is H; F; Cl; Br; I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R8 is independently straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein Z is naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl; wherein the naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, phthalazinyl, quinoxalinyl, indolyl, benzo[b]furanyl, or benzo[b]thiophenyl may be substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein r is an integer from 0 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (xe2x88x92) enantiomer.
In one embodiment, the compound has the structure: 
In another embodiment, the compound has the structure: 
In a further embodiment, the compound has the structure: 
In yet another embodiment of the present invention variable A is 
In an embodiment of the present invention, the compound is 
In another embodiment, the compound has the structure: 
In further embodiments, the compound has the structure: 
In an embodiment, the compound has the structure: 
In other embodiments, A is 
In an embodiment of the invention, the compound has the structure: 
In other embodiments, the compound has the structure: 
In additional embodiments, the compound has the structure: 
In one embodiment of the present invention, the compound has the structure: 
In another embodiment of the instant invention, A is 
In other embodiments of the invention, the compound has the structure: 
In an embodiment, the compound has the structure: 
In another embodiment, the compound has the structure: 
In yet another embodiment, the compound has the structure: 
In an embodiment, A is 
In a further embodiment, the compound has the structure 
In another embodiment, the compound has the structure: 
In yet another embodiment, the compound has the structure: 
In an additional embodiment, the compound has the structure: 
In other embodiments, A is 
In an embodiment, the compound has the structure: 
In yet another embodiment, the compound is (+)-1,2,3,6-tetra-hydro-1-{n-[4-(3,-acetamido)-phenylpiperidin-1-yl]propyl}carboxamido-4-methoxymethyl-6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5-carboxylic acid methyl ester. In a further embodiment, the compound is (xe2x88x92)-1,2,3,6-tetra-hydro-1-{n-[4-(3,-acet-amido)-phenylpiperidin-1-yl]propyl}carboxamido-4-methoxymethyl-6-(3,4-difluoro-phenyl)-2-oxopyrimidine-5-carboxylic acid methyl ester.
In a further embodiment, the compound is: 
In a further embodiment, the compound has the structure: 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94SR3; xe2x80x94CO2R3; or xe2x80x94OR3;
wherein each R1 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein each R2 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; or aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein M is aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein X is (CH2)n, O, S or NR3;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein m is an integer from 0 to 4 inclusive;
wherein n is an integer from 0 to 6 inclusive;
wherein p is an integer from 1 to 4 inclusive;
wherein q is an integer from 1 to 3 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (xe2x88x92) enantiomer.
In an embodiment, the compound has the structure: 
In a further embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (OH2)qOR3; or (CH2)qSR3.
In another embodiment, the compound has the structure 
In one embodiment, the compound has the structure: 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CON(R3)2;
wherein each R1 is independently xe2x80x94H; F; Cl; Br; I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein W is
(a) C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl optionally substituted with one or more COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl; or
(b) aryl or heteroaryl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein n is an integer from 0 to 2 inclusive;
wherein p is an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment the compounds of this invention comprise the (+) enantiomer. In another embodiment, the compounds comprise the (xe2x88x92) enantiomer.
In an additional embodiment, the compound has the structure: 
In a further embodiment, the compound has the structure 
In yet another embodiment, W is phenyl optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; or straight chained or branched C1-C7 alkyl groups.
In yet another embodiment, the compound has the structure 
In the present invention, the term xe2x80x9carylxe2x80x9d includes phenyl and naphthyl and the term xe2x80x9cheteroarylxe2x80x9d is used to include five and six membered unsaturated rings that may contain one or more heteroatoms such as oxygen, sulfur, and nitrogen. Examples of heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
In addition the term xe2x80x9cheteroarylxe2x80x9d is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen. Examples of such heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo[b]furanyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, imidazo[2,1-b]thiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, and 2,1,3-benzothiazolyl.
Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the acids and bases listed herein. The salts include, but are not limited to the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The salts include, but are not limited to the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The salts include, but are not limited to the inorganic base, ammonia. The salts include, but are not limited to the following organic bases: methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
The present invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound. Thus, in the present invention, the term xe2x80x9cadministeringxe2x80x9d shall emcompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
This invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier. In one embodiment, the amount of the compound is an amount from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 500 mg. In another embodiment, the amount of the compound is an amount from about 0.01 mg to about 250 mg. In another embodiment, the amount of the compound is an amount from about 0.1 mg to about 60 mg. In another embodiment, the amount of the compound is an amount from about 1 mg to about 20 mg. In a further embodiment, the carrier is a liquid and the composition is a solution. In another embodiment, the carrier is a solid and the composition is a tablet. In a further embodiment, the carrier is a gel and the composition is a suppository.
This invention provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
This invention provides a process for making a pharmaceutical composition comprising combining a therapeutically effective amount of the compound of this invention and a pharmaceutically acceptable carrier.
In the practice of this invention the xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.
In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents (for example, enough saline or glucose to make the solution isotonic), bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
The present invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound has the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)nNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR5; xe2x80x94OR3; or R1 and R2 together form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; O; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; O; C(R3)2; or NR3;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; xe2x80x94XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R7 is xe2x80x94H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In one embodiment, the compound has the structure 
In a further embodiment, the compound has the structure 
In an additional embodiment, the compound has the structure 
In a further embodiment, at least one R5 group is an aryl or heteroaryl group optionally substituted with one or more F; Cl; Br; I; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94XCOR8; or straight chained or branched C1-C7 alkyl.
In another embodiment, A is: 
In further embodiments, the compound is selected from the group consisting of: 
In other embodiments, the compound has the structure 
In a further embodiment, the compound has the structure 
In additional embodiments, A is 
and R7 is phenyl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)SR3; xe2x80x94XCOR8; or straight chained or branched C1-C7 alkyl.
In one embodiment, the compound has the structure 
In an embodiment of the present invention, the compound has the structure 
In yet another embodiment, the compound has the structure 
In further embodiments, A is 
and Z is O or CH2.
In an additional embodiment, the compound is selected from the group consisting of 
In one embodiment, the compound has the structure 
In a further embodiment, the compound has the structure 
In another embodiment, A is 
In yet another embodiment, the compound is 
In a further embodiment, the compound has the structure 
In another embodiment, the compound has the structure 
In yet another embodiment, the compound has the structure 
In one embodiment, the compound has the structure 
In another embodiment, the compound has the structure 
In another embodiment, the compound has the structure 
This invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound effective to reduce the body mass of the subject wherein the compound has the structure: 
wherein A is 
wherein each of Y1, Y2, Y3, Y4 and Y5 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; xe2x80x94OR3, xe2x80x94OCOR3, xe2x80x94COR3, xe2x80x94CON(R3)2, or xe2x80x94COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;
wherein each X is independently S; O; or NR3;
wherein R1 is xe2x80x94H; xe2x80x94NO2; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94CON(R3)2; or CO2(CH2)nV;
wherein R2 is xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; xe2x80x94CN; xe2x80x94CH2XR3, xe2x80x94CH2X(CH2)pNHR3, xe2x80x94(CH2)nNHR3, xe2x80x94CH2X(CH2)pN(R3)2, xe2x80x94CH2X(CH2)pN3, xe2x80x94CH2X(CH2)pNHCXR5; xe2x80x94OR3; or wherein R1 and R2 together form a lactone ring;
wherein each R3 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R4 is 
wherein each R is independently xe2x80x94H; xe2x80x94F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; xe2x80x94N(R3)2; xe2x80x94NO2; xe2x80x94CN; xe2x80x94CO2R3; xe2x80x94OR3; or xe2x80x94CN(R3)2;
wherein B is N or CY4;
wherein each D is independently C(R3)2; O; S; NR3; CO; or CS;
wherein each U is independently aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein V is C(R5)2; CR5R6; NR5 or NR6;
wherein W is CR5; CR6 or N;
wherein Z is S; O; C(R3)2; or NR3;
wherein each R5 is xe2x80x94H; xe2x80x94NO2; xe2x80x94N3; xe2x80x94CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; xe2x80x94XCOR8; or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein each R6 is independently xe2x80x94H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2;
wherein R7 is xe2x80x94H; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; xe2x80x94XCOR8; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or aminoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R8 is xe2x80x94H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94(CH2)pOR3; xe2x80x94COR3; xe2x80x94CO2R3; or xe2x80x94CON(R3)2; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR3; CO2R3; xe2x80x94CON(R3)2; CN; xe2x80x94NO2; xe2x80x94N(R3)2; xe2x80x94OR3; xe2x80x94SR3; (CH2)qOR3; (CH2)qSR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein b is 1 or 2;
wherein d is an integer from 0 to 2 inclusive;
wherein each m is independently an integer from 0 to 3 inclusive;
wherein each n is independently an integer from 0 to 5 inclusive;
wherein each p is independently an integer from 1 to 7 inclusive;
wherein q is an integer from 1 to 3 inclusive;
wherein t is an integer from 2 to 6 inclusive;
or a pharmaceutically acceptable salt thereof.
In addition, the present invention provides a method of treating a subject suffering from depression and/or anxiety which comprises administering to the subject a compound of the aforementioned formula in an amount effective to treat the subject""s depression and/or anxiety.
This invention also provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound effective to decrease the consumption of food by the subject wherein the compound is selected from the group consisting of: 
This invention further provides a method of modifying feeding behavior of a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject.
This invention also provides a method of treating a feeding disorder in a subject which comprises administering to the subject an amount of a compound of the present invention effective to decrease the consumption of food by the subject. In an embodiment of the present invention, the feeding disorder is bulimia, obesity or bulimia nervosa. In a further embodiment, the subject is a vertebrate, a mammal, a human or a canine. In yet another embodiment, the compound is administered in combination with food.
In the subject invention a xe2x80x9ctherapeutically effective amountxe2x80x9d is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for treating the above noted disorders.
Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
This invention further provides compositions which need not be pharmaceutical as that term is understood in the art. Such compositions comprise a compound in accordance with the subject invention in an amount effective to antagonize an MCH1 receptor and a suitable carrier.
Still further, the invention provides a method of agonizing and/or antagonizing an MCH1 receptor which comprises contacting the receptor, e.g. in vitro or in in vivo, with an amount of a compound of this invention effective to agonize and/or antagonize the receptor.
This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.